The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder

Bossé, Gabriel D.; Cadeddu, Roberto; Floris, Gabriele; Farero, Ryan D.; Vigato, Eva; Zhang, Tejia; Gaikwad, Nilesh W.; Keefe, Kristen A.; Phillips, Paul E. M.; Bortolato, Marco; Peterson, Randall T.

doi:10.1172/jci143990

Cited by 14 publications

(8 citation statements)

References 90 publications

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“…Stereotaxic surgery and microinjections. Stereotaxic surgery was performed as previously described (Cadeddu et al, 2021). Briefly, mice were anesthetized with xylazine/ketamine (20/80 mg•kg -1 , IP) and then placed onto a stereotaxic frame (David Kopf Instruments, Tujunga, CA, USA).…”

Section: Stress Proceduresmentioning

confidence: 99%

Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex

Cadeddu

Mosher

Nordkild

et al. 2022

Preprint

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Background and purpose: Ample evidence indicates that environmental stress impairs information processing, yet the underlying mechanisms remain partially elusive. We showed that, in several rodent models of psychopathology, the neurosteroid allopregnanolone (AP) reduces the prepulse inhibition (PPI) of the startle, a well-validated index of sensorimotor gating. Since this GABAA receptor activator is synthesized in response to acute stress, we hypothesized its participation in stress-induced PPI deficits. Experimental approach: We studied whether and how AP influences PPI in mice and rats; thereafter, we tested AP's implication in the PPI deficits produced by several complementary regimens of acute and short-term stress (footshock, restraint, predator exposure, and sleep deprivation). Key results: Systemic AP administration reduced PPI in C57BL/6J mice and Long-Evans, but not Sprague-Dawley, rats. These effects were reversed by isoallopregnanolone (isoAP), an endogenous AP antagonist, and the GABAA receptor antagonist bicuculline and mimicked by AP infusions in the medial prefrontal cortex (mPFC). PPI was reduced by acute footshock, sleep deprivation as well as the combination of restraint and predator exposure in a time- and intensity-dependent fashion. Acute stress increased AP concentrations in the mPFC, and its detrimental effects on PPI were countered by systemic and intra-mPFC administration of isoAP. Conclusions and implications: These results collectively indicate that acute stress impairs PPI by increasing AP content in the mPFC. The confirmation of these mechanisms across distinct animal models and several acute stressors strongly supports the translational value of these findings and warrants future research on the role of AP in information processing.

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Section: Stress Proceduresmentioning

confidence: 99%

Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex

Cadeddu

Mosher

Nordkild

et al. 2022

Preprint

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“…Recently, the group of Peterson reported that NHE1 inhibitors could reduce opioid self-administration in a zebrafish model. 49 Although preliminary, it could be very interesting to test whether this result is mediated by NHE1, or a direct allosteric effect on opioid receptors, or both simultaneously. Many GPCRs interact with the Na(+)/H(+) exchange regulatory cofactor (NHERF-1/2), which was originally characterized as a cAMP-dependent regulator of Na(+)/H(+) exchange (NHE).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Sodium Channel Inhibitors at the Delta-Opioid Receptor

et al. 2022

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Existing pharmacotherapies acting on the opioid receptor system have been extensively used to treat chronic pain and addictive disorders. Nevertheless, the adverse side effects associated with opioid therapy underscore the need for concerted measures to develop safer analgesics. A promising avenue of research stems from the characterization of a sodium-dependent allosteric regulation site housed within the delta-opioid receptor and several other G protein-coupled receptors (GPCRs), thereby revealing the presence of a cluster of sodium and water molecules lodged in a cavity thought to be present only in the inactive conformation of the receptor. Studies into the structure–function relationship of said pocket demonstrated its critical involvement in the functional control of GPCR signaling. While the sodium pocket has been proposed to be present in the majority of class A GPCRs, the shape of this allosteric cavity appears to have significant structural variation among crystallographically solved GPCRs, making this site optimal for the design of new allosteric modulators that will be selective for opioid receptors. The size of the sodium pocket supports the accommodation of small molecules, and it has been speculated that promiscuous amiloride and 5′-substituted amiloride-related derivatives could target this cavity within many GPCRs, including opioid receptors. Using pharmacological approaches, we have described the selectivities of 5′-substituted amiloride-related derivatives, as well as the hitherto undescribed activity of the NHE1 inhibitor zoniporide toward class A GPCRs. Our investigations into the structural features of the delta-opioid receptor and its ensuing signaling activities suggest a bitopic mode of overlapping interactions involving the orthosteric site and the juxtaposed Na + pocket, but only at the active or partially active opioid receptor.

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“…163,164 Interestingly, the findings of antidopaminergic properties of finasteride also led to the discovery of other potential therapeutic application of 5αR inhibitors in animal models of other motor disturbances, such as levodopa-induced dyskinesias, 165,166 as well as in opioid use disorder. 167 It is worth noting that the antidopaminergic effects of finasteride are not associated with extrapyramidal side effects, such as catalepsy, 161 likely a result of the interference with D 1 , rather than D 2 dopamine receptor signalling.…”

Section: Preclinical Findingsmentioning

confidence: 99%

“…107 This possibility is indirectly supported by preliminary data indicating that finasteride reduces impulsivity 173 and pathological gambling. 157 In addition, we recently documented that finasteride also potently reduces opioid self-administration, 167 another response highly influenced by impulsivity. Assuming that AP can reduce the prefrontal control of striatal outputs, this mechanism may also be responsible for a disinhibitory effect, which may account for the exacerbation of impulsive behaviours in response to acute stress.…”

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?

Bortolato

Coffey

Gabbay

et al. 2021

J Neuroendocrinology

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The neurosteroid allopregnanolone (3α‐hydroxy‐5α‐pregnan‐20‐one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti‐inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABAA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors. In keeping with this evidence, AP has been shown to exert rapid, potent antidepressant properties and has been recently approved for the therapy of moderate‐to‐severe postpartum depression. In addition to depression, emerging evidence points to the potential of AP as a therapy for other neuropsychiatric disorders, including anxiety, seizures, post‐traumatic stress disorder and cognitive problems. Although this evidence has spurred interest in further therapeutic applications of AP, some investigations suggest that this neurosteroid may also be associated with adverse events in specific disorders. For example, our group has recently documented that AP increases tic‐like manifestations in several animal models of tic disorders; furthermore, our results indicate that inhibiting AP synthesis and signalling reduces the exacerbation of tic severity associated with acute stress. Although the specific mechanisms of these effects remain partially elusive, our findings point to the possibility that the GABAergic activation by AP may also lead to disinhibitory effects, which could interfere with the ability of patients to suppress their tics. Future studies will be necessary to verify whether these mechanisms may apply to other externalising manifestations, such as impulse‐control problems and manic symptoms.

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The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder

Cited by 14 publications

References 90 publications

Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex

Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex

Functional Characterization of Sodium Channel Inhibitors at the Delta-Opioid Receptor

Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?

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